The US Food and Drug Administration (FDA) on Tuesday released a revised version of its draft guidance on direct-acting antiviral (DAA) Hepatitis C virus (HCV) drugs, which calls on sponsors to conduct head-to-head Phase III studies for drugs in development.
FDA says the draft guidance only applies to drugs with a mechanism that interferes with HCV replication, "through a direct interaction with the HCV genome, polyprotein, or its polyprotein cleavage products," and does not cover new immune-based drugs or those that work to prevent or reverse outcomes of chronic HCV.
Since FDA last revised the guidance in October 2013, there has been a massive shift in the treatment of HCV, brought on by a new generation of cures reaping tens of billions of dollars in sales, including Gilead's Sovaldi (sofosbuvir) and Harvoni (ledipasvir and sofosbuvir), AbbVie's Viekra Pak (ombitasvir, paritaprevir, ritonavir and dasabuvir) and Technivie (ombitasvir, paritaprevir and ritonavir) and Merck's Zepatier (elbasvir and grazoprevir).
Prior to the development of DAA drugs to treat HCV, standard treatment involved a combination of pegylated interferon and ribavirin over the course of 24 or 48 weeks, depending on the specific HCV genotype being treated. However, current generation DAA drugs are able to cure upwards of 90% of patients, without the use of interferon, in as little as 12 weeks.
Due to these vast improvements, FDA says it was necessary to revise its guidance to focus more heavily on interferon-free regimens, provide more detailed recommendations for Phase II and Phase III clinical trials and clarify expectations for trial design for patients with other comorbidities, including co-infection with human immunodeficiency virus-1 (HIV-1) and advanced chronic kidney disease.
Significantly, FDA says it now expects sponsors of new HCV DAAs to conduct at least one head-to-head Phase III trial against an approved comparator.
"Ideally … an active comparator in a Phase III, controlled trial should be an antiviral drug that is recommended for treatment of chronic HCV infection by authoritative scientific bodies based on clinical evidence that also reflects current practice," FDA writes.
However, in cases where there are no interferon-free options for a given population, FDA says that "single-arm trials using a historical control may be appropriate."
Additionally, due to the success of recent interferon-free DAA drugs for HCV, FDA says it no longer recommends drugmakers study DAAs in combination with interferon for DAA treatment-naïve patients.
Because most DAAs are used in combination with other HCV drugs, FDA says sponsors must characterize the antiviral activity relationship between the drugs during preclinical testing.
If studying a HCV DAA combination in HIV positive patients, FDA also recommends sponsors conduct a similar assessment to determine the antiviral activity relationship with HIV drugs that operate on a similar mechanism of action.
Additionally, to improve a combination's odds against existing and emerging drug-resistant strains of HCV, FDA says sponsors should select a combination of "multiple anti-HCV drugs with non-overlapping resistance pathways."
Chronic Hepatitis C Virus Infection: Developing Direct-Acting Antiviral Drugs for Treatment